Skull Base Closure Systems And Methods

ABSTRACT

The present disclosure provides a bioresorbable foam closure device for trans-nasally closing an opening in a base of a skull. The closure device comprises a phase-separated polymer having a porosity of greater than 80%. The device includes a stem portion having a proximal end and a distal end, and a head portion at the distal end of the stem portion. The closure device is deformed from a free shape to a constricted shape, inserted through a nasal cavity and into the opening, and released to at least partially revert back to the free shape such that the stem portion fills the opening and the head portion abuts cranium and dura to secure the closure device in position and seal the opening.

CROSS-REFERENCE TO RELATED APPLICATIONS

The subject application claims priority to and all of the benefits ofU.S. Provisional Patent Application No. 62/782,718, filed on Dec. 20,2018, the disclosure of which is hereby incorporated by reference.

BACKGROUND

Trans-nasal skull based surgical techniques have advanced significantlyover the years. Repairing large skull base openings and cerebrovascularstructures resulting from trans-nasal skull based surgical techniques,e.g. endoscopic trans-nasal craniotomies, remains a difficult challenge.Problems with closure of the skull defect which typically includes acompromised dura mater and prevention of cerebrospinal fluid leaks are apersistent source of complications in both endoscopic and open skullbased surgeries. As such, there remains a need for improved materialsand methods, which may be used to prevent post-surgical cerebrospinalfluid leaks and promote the repair of large skull base openings andcerebrovascular structures resulting from skull based surgeries.

SUMMARY

The present disclosure provides a bioresorbable foam closure device fortrans-nasally closing an opening in a base of a skull. The closuredevice includes a phase-separated polymer having a porosity of greaterthan 50%. The device includes a stem portion having a proximal end and adistal end, and a head portion at the distal end of the stem portion.

The present disclosure also provides a surgical tool for placing theclosure device in an opening in a base of a skull. The surgical toolincludes a body defining an inner channel. The body has a handle, adispensing tip, and a central section therebetween. The dispensing tiphas a tapered profile between a first region and a second region, withthe first region having a greater diameter than the second region. Ashaft is moveably disposed in the inner channel of the body, the shafthas a control surface at a proximal region and a deformable head at adistal region, the shaft and the deformable head cooperate to define alumen to accommodate a portion of the closure device. Upon actuation ofthe control surface, the deformable head moves between a first state inwhich the deformable head is outside of the second region of thedispensing tip and a second state where the deformable head is at leastpartially within the second region of the dispensing tip. A diameter ofthe deformable head in the first state is greater than a diameter of thedeformable head in the second state.

A method of trans-nasally closing an opening in a base of a cranium withthe closure device and the surgical tool is further disclosed. Themethod includes the steps of providing the closure device. At least thehead portion of the closure device is deformed from a free shape to adeformed shape. Once deformed, the head portion is inserted through anasal cavity and through the opening such that the head portion is inthe cranial cavity and the stem portion extends through the opening andinto the nasal cavity. Once released, the closure device at leastpartially reverts to the free shape such that the stem portion fills theopening and the head portion abuts an inner surface of the cranium aswell as dura, thereby securing the closure device in position andsealing the opening.

As such, the subject disclosure provides improved materials and methods,which may be used to prevent post-surgical cerebrospinal fluid leaks andpromote the repair of large skull base openings, and cerebrovascularstructures resulting from skull based surgeries.

BRIEF DESCRIPTION OF THE DRAWINGS

Advantages of the present disclosure will be readily appreciated as thesame becomes better understood by reference to the following detaileddescription when considered in connection with the accompanying drawingswherein:

FIG. 1 is a perspective view of an exemplary bioresorbable foam closuredevice for trans-nasally closing an opening in a base of a skull;

FIG. 2 is a cross-sectional view along 2-2 of the closure device of FIG.1;

FIG. 3 is a perspective view of another exemplary bioresorbable foamclosure device for trans-nasally closing an opening in a base of askull;

FIG. 4 is a cross-sectional view along 4-4 of the closure device of FIG.3;

FIG. 5 is a perspective view of an exemplary surgical tool for placingthe closure device in an opening in a base of a skull;

FIG. 6 is a cross-sectional view along 6-6 of the surgical tool of FIG.5;

FIG. 7A is a perspective view of the closure device and the surgicaltool prior to loading the closure device in the surgical tool;

FIG. 7B is cross-sectional view along 7B-7B of the closure device and adistal end of the surgical tool prior to loading;

FIG. 8A is a perspective view of the closure device loaded into a distalend of the surgical tool;

FIG. 8B is cross-sectional view along 8B-8B of the closure device loadedinto the distal end of the surgical tool;

FIG. 9 is a perspective view of another exemplary surgical tool forplacing a closure device in an opening in a base of a skull, thesurgical tool having a flexible central section that allows a shape ofthe surgical tool to be changed to facilitate use of the surgical toolin a nasal cavity;

FIG. 10 is a perspective view of the closure device loaded into thesurgical tool as well as an opening in a base of a skull;

FIG. 11 is a cross-sectional view of the deformed closure device loadedinto a surgical tool, which is aligned with and partially in the openingin the base of the skull;

FIG. 12 is a cross-sectional view of the surgical tool inserted in theopening in the base of the skull with the deformed closure devicepartially released from the surgical tool;

FIG. 13 is a cross-sectional view of the surgical tool inserted in theopening in the base of the skull with the deformed closure device fullyreleased from the surgical tool;

FIG. 14 is a cross-sectional view of the released closure device atleast partially reverted back to its free shape such that the stemportion fills the opening and the head portion abuts an inner surface ofthe cranium as well as dura, thereby securing the closure device inposition and sealing the opening; and

FIG. 15 is a flow diagram generally illustrating steps included in amethod of trans-nasally closing the opening in the base of theskull/cranium with the closure device.

It is to be understood that the drawings are purely illustrative and arenot necessarily drawn to scale.

DETAILED DESCRIPTION

Examples of a bioresorbable foam closure device (“closure device”) 10for trans-nasally closing an opening 300 in a base of a skull 302 areshown in FIGS. 1-4. The closure device 10 includes a stem portion 12having a proximal end 14 and a distal end 16. The closure device 10 alsoincludes a head portion 18 adjacent the distal end 16 of the stemportion 12.

As is explained herein, during use, the closure device 10 is deformedfrom a free shape to a constricted shape, inserted through a nasalcavity 298 and into the opening 300, and released to at least partiallyrevert back to the free shape such that the stem portion 12 fills theopening 300 and the head portion 18 abuts an inner surface 304 of theskull/cranium 302 as well as dura 308, thereby securing the closuredevice 10 in position to close and seal the opening 300. Use of theclosure device 10 is described in detail below and illustrated in FIGS.10-13.

Referring now to FIG. 1, the distal end 16 of the stem portion 12 havingthe head portion 18 thereon is furthest from the surgeon, while theproximal end 14 of the stem portion 12 is closest to the surgeon. Inother words, when the closure device 10 is inserted into the nasalcavity 298, the head portion 18 and the distal end 16 of the stemportion 12 are the first end to enter the nasal cavity 298 and theproximal end 14 of the stem portion 12 is relatively close to thesurgeon.

The head portion 18 typically has at least one dimension, e.g. a radius,which is larger than a dimension of the stem portion 12. Referring againto FIG. 1, the head portion 18 and the stem portion 12 may share alongitudinal axis A_(L). In certain shapes, the radius R_(H) of the headportion 18 relative to the longitudinal axis A_(L) is greater than theradius R_(S) of the stem portion 12 relative to the longitudinal axisA_(L). In the example shown in FIGS. 1 and 2, the stem portion 12 thehead portion 18 have a cylindrical shape. More specifically, in theexample of FIG. 1, the stem portion 12 is cylindrical and the headportion is concentrically disposed on the distal end 16 of the stemportion 12 and disc shaped (cylindrical). The geometric configuration ofthe stem portion 12 is not particularly limited. Although the stemportion 12 throughout the Figures is illustrated as cylindrical with acircular cross-sectional profile, it should be appreciated that the stemportion 12 and the head portion could have various cross-sectionalprofiles including but not limited to ovular (including circular),rectangular (including square), and triangular.

In some examples, the stem portion 12 may include a core portion and ashell portion (not illustrated in the Figures). In one example, the coreportion and the shell portion are foamed. The shell portion is arrangedsuch that the foamed core portion is at least partially disposed withinthe foamed shell portion. Within the context of this disclosure “atleast partially disposed within” requires that some volume of the coreportion is disposed within a cavity of the shell portion. In certainexamples, from 10 to 100%, from 20 to 100%, from 30 to 100%, from 40 to100%, from 50 to 100%, from 60 to 100%, from 70 to 100%, from 80 to100%, or from 90 to 100%, of the total volume of the core portion isdisposed within the shell portion. In one such example, the shellportion and core portion are adjacent laminar layers.

The closure device 10 of some examples may be shaped with the stemportion 12 of excess length and the head portion 18 of excess area. Suchexamples allow a user, e.g. a doctor, to tailor the shape of the closuredevice 10 to a particular nasal cavity 298 and a particular opening 300by simply cutting the closure device 10 to a desired shape based on theparticular opening 300 to be sealed. Of course, the materials from whichthe closure device 10 of such examples are formed are selected such thatthey may be cut to the desired shape with surgical scissors, a surgicalknife, etc.

As is alluded to above, the closure device 10 is deformable and shapedto close and seal the opening 300 in the skull 302, with the stemportion 12 filling the opening 300 and the head portion 18 abutting theinner surface 304 of the skull/cranium 302. To this end, the headportion 18 may be foldable or collapsible along the longitudinal axisA_(L) in the distal direction. Alternatively, the head portion may befoldable along a different line/plane. Alternatively, the head portionmay be deformable in a manner other than folding. FIG. 7 illustrates thehead portion 18 in a free state whereas FIG. 8 illustrates the headportion 18 in a constricted state.

The head portion 18 has a greater perimeter and/or diameter than thestem portion 12. In the example of FIG. 1, the head portion 18 is discshaped and has both a greater perimeter and diameter than the stemportion 12. The geometric configuration of the head portion 18 is notparticularly limited. Although the head portion 18 is illustratedthroughout the Figures as having a round cross-sectional profile, itshould be appreciated that the head portion 18 could have variouscross-sectional profiles including but not limited to ovular (includingcircular), rectangular (including square), and triangular.

In the example of FIG. 1, the head portion 18 includes a film layer 20comprising polymer and a foam base 22 comprising the phase-separatedpolymer. The film layer 20 and the foam base 22 form a bond interface 24therebetween. The film layer 20 is disposed at the distal end 16 of theclosure device 10 and the foam base 22 is disposed between the filmlayer 20 and the distal end 16 of the stem portion 12 of the closuredevice 10. When arranged in this manner, the film layer 20 acts as animpermeable or semi-permeable membrane to stop the leakage ofcerebrospinal fluid and promote the repair of the opening 300. As such,the film layer 20 may have a porosity less than a porosity of the foambase 22. In some examples, the film layer 20 comprises polysiloxane. Inother examples, film layer 20 comprises polyurethane. The film layer maycomprise alternative polymers as well.

The closure device 10 may include a phase-separated polymer having aporosity of greater than 50%. In a typical example, the stem portion 12and the foam base 22 of the head portion 18 each include thephase-separated polymer. Of course, the stem portion 12 and the headportion 18 may include different phase-separated polymers. Further, ifthe stem portion 12 includes sub portions, these sub portions mayinclude the same or different phase-separated polymers.

In other words, the phase-separated polymer in each particular portionmay be different. For example, a first phase-separated polymer havinglower porosity and more resilience may be used in the head portion 18 ofthe closure device 10 while a second phase-separated polymer havinggreater porosity and greater compressibility may be used to form thestem portion 12. In addition to the porosity, foam density establishesthe physical properties of the particular portion. Porosity and foamdensity can be balanced to achieve good compressibility, which meansthat the foamed phase-separated polymer retains its structure (inparticular its compression strength) when having absorbed or beingsaturated with a liquid, such as blood. The mechanical, structural andchemical properties of the foamed phase-separated polymer are mainlydetermined by the composition (structure) of polymer used. To this end,selection of the reactants used to form the phase-separated polymerprovides a way to control and adjust the mechanical, structural andchemical properties of the phase-separated polymer.

The properties of the particular portions of the closure device 10 are,in many examples, tailored to swell (or not swell) upon exposure tomoisture within the nasal cavity and inter cranial space. To this end,the stem portion 12 may be formed from a phase-separated polymer that ishydrophilic, while the head portion 18 and film layer 20 may be formedfrom a phase-separated polymer which is hydrophobic. Of course, the stemportion 12, the head portion 18, and the film layer 20 can be eitherhydrophilic or hydrophobic. In some configurations, poly(ethyleneglycol) is avoided for use in the phase-separated polymer becauseswelling may increase the pressure within the cranial cavity 310(intracranial pressure/ICP). As such, some examples of the closuredevice 10 include the head portion 18 and the film layer 20 which isless hydrophilic and relatively less porous than the stem portion 12. Inother examples, the closure device 10 includes the head portion 18 andthe film layer 20 which are extensively physically cross-linked, or havesignificant hydrogen bonding (e.g. polyurethane which is hydrogen bondedas is described below) and use low molecular weight poly(ethyleneglycol).

The phase-separated polymer may be biodegradable or bioresorbable. Theterm “biodegradable” as used herein, refers to the ability of a polymerto be acted upon biochemically in general by living cells, organisms, orpart of these systems, including hydrolysis, and to degrade anddisintegrate into chemical or biochemical products. Further, the term“bioresorbable” as used herein, refers to the ability of beingmetabolized by the human or animal body.

The term “phase-separated polymer” as used herein, refers to a polymercomprising soft (amorphous) segments, as well as hard (crystalline)segments, the hard segment having a phase transition temperature of atleast mammalian body temperatures (which is generally 37° C. for humans)and the phase-separated morphology being manifest when the foam preparedfrom such a polymer is applied in the human or animal body for asufficient period of time. In addition, the polymer placed undertemperature conditions comparable to the human or animal body exhibitsthe phase-separated morphology. A phase-separated polymer ischaracterized by the presence of at least two immiscible or partlymiscible phases with a different morphology at normal environmentalconditions. Within one material, a rubber phase and a crystalline phase(at a temperature above the glass transition temperature of theamorphous phase and below the melting temperature of the crystallinephase) may be present or a glassy and a crystalline phase (at atemperature below the glass transition temperature of the amorphousphase). Also at least two amorphous phases may be present at atemperature between the two phase transitions, e.g. one glassy and onerubbery phase. At a temperature above the highest phase transition,which is either a melting or glass transition temperature, the liquidand rubbery or the two rubbery phases, respectively, may form a phasemixed morphology or they may still be immiscible. Immiscible liquidand/or rubbery phases usually results in a polymer with aphase-separated morphology without the initial desired mechanicalproperties at normal environmental conditions.

In some examples, the phase-separated polymer has a porosity of greaterthan 50, 60, 70, or 80%. Alternatively, the phase-separated polymer hasa porosity from 30 to 99%, from 40 to 99%, from 50 to 96%, from 60 to96%, from 70 to 96%, from 80 to 93%, from 80 to 90%, from 80 to 87%,from 80 to 84%, from 83 to 99%, from 85 to 99%, from 89 to 99%, from 92to 99%, from 95 to 99%, from 83 to 96%, from 86 to 93%, from 92-98%, orfrom 95-98%.

In some examples, the phase-separated polymer has a foam density of 0.01to 1.0 g/cm³. Alternatively, the foam density may be from 0.01 to 0.5,0.01 to 0.3, 0.01 to 0.1, 0.01 to 0.09, 0.01 to 0.08, 0.01 to 0.07, 0.01to 0.06, 0.01 to 0.05, 0.01 to 0.04, 0.01 to 0.03, 0.02 to 0.08, 0.04 to0.08, 0.05 to 0.08, 0.06 to 0.08, 0.02 to 0.08, or 0.03-0.07 g/cm³. Incertain examples, the phase-separated polymer has a porosity of 85-99%and a foam density of 0.03-0.07 g/cm³. It is to be appreciated that theterm “foam density” as used throughout this disclosure refers to thedensity of foam, calculated as the phase-separated polymer mass pervolume unit of particular foam portion. Accordingly, if the particularfoamed portion includes an active agent, the mass of the active agentpresent in the particular foamed portion is disregarded when calculatingthe foam density.

The phase-separated polymer may be selected from the group consisting ofpolyesters, polyethers, polyhydroxyacids, polylactones, polyetheresters,polycarbonates, polydioxanes, polyanhydrides, polyurethanes,polyester(ether)urethanes, polyurethane urea, polyamides,polyesteramides, poly-orthoesters, polyaminoacids, polyphosphonates,polyphosphazenes and combinations thereof. Such polymers are describedin WO 99/64491 A1, which is incorporated by reference in its entirety.

As is described above, the phase-separated polymer includes soft(amorphous) segments, as well as hard (crystalline) segments. The term“amorphous” as used herein, refers to segments present in thephase-separated polymer with at least one glass transition temperaturebelow the temperature of the cavities of the human or animal body intowhich the foam is packed, and may also refer to a combination of anamorphous and crystalline segment which is completely amorphous whenpacked in the human or animal body. For example, PEG in a pre-polymermay be crystalline in pure form but may be amorphous when included inthe R segment of a polyurethane of the formula (I). Longer PEG segmentsmay also be partly crystalline when included in the R segment of apolyurethane of the formula (I) but will become amorphous (“dissolves”)when placed in contact with water. Therefore, such longer PEG segmentsare part of the soft segment of the phase-separated polymer of theformulas (I), whereas the hard segment should remain crystalline innature to provide sufficient support for a particular foamed portion inthe wet and packed state for a certain period of time.

The term “crystalline” as used herein, refers to segments, present inthe phase-separated polymer, that are crystalline when packed in thehuman or animal body, i.e., that have a melting temperature above thetemperature of the human or animal body into which the closure device 10is inserted.

A “hydrophilic segment” as used herein, refers to a segment comprisingat least one, preferably at least two, more preferably at least threehydrophilic groups such as may be provided for instance by C—O—C, orether, linkages. A polyether segment may thus provide a hydrophilicsegment. A hydrophilic segment may also be provided by polypeptide,poly(vinyl alcohol), polyvinylpyrrolidone) orpoly(hydroxyethylmethacrylate). A hydrophilic segment is preferablyderived from polyalkyleneglycol, such as polyethyleneglycol,polypropyleneglycol, or polybutyleneglycol. The preferred hydrophilicsegment is a polyethyleneglycol (PEG) segment.

The term “segment” as used herein, refers to a polymeric structure ofany length. In the art of polymer technology, a long polymeric structureis often referred to as a block, whereas a short polymeric structure isoften referred to as a segment. Both these conventional meanings areunderstood to be included in the term “segment” as used herein.

In one particular example of the present application, thephase-separated polymer is of the formula:

—[R-Q¹[-R′—Z¹—[R″—Z²—R′—Z³]_(p)—R″—Z⁴]_(q)—R′-Q²]_(n)-  (I)

wherein R is selected from one or more aliphatic polyesters,polyetheresters, polyethers, polyanhydrides and/or polycarbonates, andoptionally at least one R includes a hydrophilic segment, R′ and R″ areindependently C2-C8 alkylene, optionally substituted with C1-C10 alkylor C1-C10 alkyl groups substituted with halides or protected S, N, P orO moieties and/or comprising S, N, P or O in the alkylene chain, Z1-Z4are independently amide, urea or urethane, Q1 and Q2 are independentlyurea, urethane, amide, carbonate, ester or anhydride, n is an integerfrom 5-500, p and q are independent 0 or 1, provided that when q is O, Ris at least one amorphous aliphatic polyester, polyether, polyanhydrideand/or polycarbonate segment with optionally at least one crystallinepolyether, polyester, polyetherester or polyanhydride segment.

The simplest form of the phase-separated polymer, as represented byformula I, is of the formula: —R— Q¹-R′-Q²-, i.e. when q=0.

The amorphous segment is included in the —R— part of the polymeraccording to formula (I). In case q=1, theQ¹[-R′—Z¹—[R″—Z²—R′—Z³]_(p)—R″—Z⁴]_(q)—R′-Q² part of the polymeraccording to formula (I) represents the crystalline segment. In thisparticular example, the amorphous and crystalline segments arealternating, thus providing the hard segment with a uniformblock-length.

As described above, R may represent a mixture of two or more differenttypes of aliphatic polyesters, polyetheresters, polyethers,polyanhydrides and/or polycarbonates, which mixture includes bothamorphous and crystalline types, so that both are included in aparticular foamed portion. In the case that a mixture of amorphous andcrystalline types of R segments are provided in a polymer according tothe formula (I), optionally at least one hydrophilic segment is providedin at least one amorphous R segment.

R may in particular be derived from the cyclic monomers lactide (L, D orLD), glycolide, c-caprolactone, δ-valerolactone, trimethylenecarbonate,tetramethylenecarbonate, 1,5-dioxepane-2-one, para-dioxanone, andcombinations thereof and optionally polyethyleneglycol,polypropyleneglycol, polybutyleneglycol and combinations thereof. Incertain examples, R is an amorphous polyester derived from exclusivelylactide and ε-caprolactone, with a molecular weight between 1000 and4000. In one example, R is about 25 wt. % lactide, about 25 wt. %ε-caprolactone and about 50 wt. % of polyethyleneglycol.

In a phase-separated polymer according to the formula (I), Q¹ and Q² maybe selected from amide, urea, urethane ester, carbonate or anhydridegroups, whereas Z¹ through Z⁴ should be chosen from amide, urea orurethane groups so that at least 4 hydrogen bond forming groups arepresent in a row in the crystalline segment. The group R′ in —Z²—R′—Z³—may be different or similar to R′ in -Q¹-R′—Z¹— or —Z⁴—R′-Q²-.

As stated, R optionally includes a hydrophilic segment and such ahydrophilic segment may very suitably be an ether segment, such as apolyether segment derivable from such polyether compounds aspolyethyleneglycol, polypropyleneglycol or polybutyleneglycol. Also, ahydrophilic segment included in R may be derived from polypeptide,poly(vinyl alcohol), polyvinylpyrrolidone) orpoly(hydroxyethylmethacrylate). A hydrophilic segment is preferably apolyether, e.g. a poly(alkylkene glycol), such as poly(ethylene glycol),poly(propylene glycol) or poly (butylene)glycol.

In certain examples, the amorphous segment includes a hydrophilicsegment. The hydrophilic segment may include polyethylene glycol in anamount of 1-80 wt %, more preferably 5-60 wt %, even more preferably20-50 wt %, most preferably 50 wt %, based on the total weight of thehydrophilic segment.

In certain examples, the phase-separated polymer is a polymer accordingto formula I, wherein R′ is (CH₂)₄, R″ is (CH₂)₄, or both R′ and R″ are(CH₂)₄. For example, Z¹-Z⁴ may be a urethane.

It should be appreciated that the foams described herein are comprisedof a plurality of polymer chains, with each of the polymer chainscomprising the phase-separated polymer, e.g. a polyurethane. In manyexamples, the foams are substantially free of any covalent cross-linkingbetween polymer chains included in the foam. In the context of thisdisclosure, the term “substantially free of any covalent cross-linking”means that one polymer chain has less than 20, less than 10, less than6, less than 4, or less than 2 covalent bonds to other polymer chainsincluded in the foam. In some examples, the foam is free of any covalentcross-linking between polymer chains included in the foam. In otherwords, each polymer chain is not covalently cross-linked to any otherpolymer chain included in the foam.

In some preferred examples, the phase-separated polymer is apolyurethane foam including amorphous segments and crystalline segments,the crystalline segments formed via hydrogen bonding. In such examples,the crystalline segments include the reaction product of 1,4 butanedioland 1,4 diisocyanatobutane, while the amorphous segments in thepolyurethane foam include a polyalkylene glycol, e.g. poly(ethyleneglycol), a polyester, e.g. polyglycolide, or a combination of the two.

The term “hydrogen bonding” as used herein, refers to a partiallyelectrostatic attraction between a hydrogen (H) atom which is bound to amore electronegative atom or group, such as nitrogen (N), oxygen (O), orfluorine (F)—the hydrogen bond donor—and another adjacent atom bearing alone pair of electrons—the hydrogen bond acceptor. In polyurethanes,hydrogen bonding between carbonyl and N—H groups is one of the majordriving forces for phase separation. Hydrogen bonds may beintermolecular (occurring between separate molecules) or intramolecular(occurring among parts of the same molecule).

In such examples, the foams described herein comprise hard/crystallineand soft/amorphous segments. The hard segments are formed via hydrogenbonding between urethane segments of each polymer chain. While notwishing to be bound by one particular theory, it is believed thaturethane segments of each polymer chain are particularly susceptible tohydrogen bonding with other urethane segments in adjacent polymerchains. Accordingly, during formation of the foam, the urethane segmentsof each polymer chain are hydrogen bonded to, and thereby aligned with,the urethane segments of other polymer chains included in the foam.Because the urethane segments of each polymer chain are aligned withurethane segments of the other polymer chains, the polyetherestersegments of each polymer chain are necessarily aligned with thepolyetherester segments of other polymer chains included in the foam.The alignment of these polyetherester segments forms the soft segmentsof the foam. As such, because of the hydrogen bonding between urethanesegments of each polymer chain, the foam exhibits a highly organizedthree-dimensional network structure of hard and soft segments.

Accordingly, the polyurethane foam of this preferred example includescrystalline segments formed via hydrogen bonding. Further, it isbelieved that the crystalline segments comprising the reaction productof 1,4 butanediol and 1,4 diisocyanatobutane and the amorphous segmentscomprising poly(ethylene glycol) form crystalline segments and theamorphous segments that “stack” in an alternating configuration toprovide a 3-dimentional porous structure which is strengthened viahydrogen bonding between the stacked crystalline segments.

Further, the polyurethane foam of this preferred example readilyinteracts with other polymers to hydrogen bond because it includes thecrystalline segments comprising the reaction product of 1,4 butanedioland 1,4 diisocyanatobutane and the amorphous segments comprisingpoly(ethylene glycol). As such, the film layer 20 may be selected from apolymer such as polyurethane or silicone such that the film layer 20 andthe foam base 22 are bonded to one another via hydrogen bonding andsubstantially free of covalent bonds therebetween. In this example,hydrogen bonding between the phase-separated polymer comprisingcrystalline segments comprising the reaction product of 1,4 butanedioland 1,4 diisocyanatobutane and amorphous segments comprisingpoly(ethylene glycol), and the film layer 20 including silanol groupsand/or urethane group occurs readily. Of course, hydrogen bondingbetween the film layer 20 and the foam base 22 eliminate the need for anadhesive therebetween. As such, in many examples, the bond interface 24between the film layer 20 and the foam base 22 is free of adhesive.

In a typical example, the removal of the film layer 20 from the foambase 22 results in cohesive failure of the foam base 22 at the bondinterface 24. The failure mode exhibited when the film layer 20 isremoved from the foam base 22 may be classified as adhesive failure,where failure occurs at the bond interface 24 between the film layer 20and the foam base 22, and cohesive failure, where the failure occurswithin the foam base 22. As such, cohesive failure may be furtherdescribed as a % area of the surface of the film layer 20 which retainsphase-separated polymer (foam) from the foam base 22 bonded thereto whenthe film layer 20 is peeled from the foam base 22. As such, in someexamples, the cohesive failure between the film layer 20 and the foambase 22 is greater than 50, 60, 70, 80, 90, or 95%. Alternatively, thecohesive failure is described as from 50 to 99%, from 50 to 96%, from 60to 96%, from 70 to 96%, from 80 to 93%, from 80 to 90%, from 80 to 87%,from 80 to 84%, from 83 to 99%, from 85 to 99%, from 89 to 99%, from 92to 99%, from 95 to 99%, from 83 to 96%, from 86 to 93%, from 92-98%,from 95-98%, or 90%. Removal of the film layer 20 from the foam base 22may be accomplished manually (via hand peeling the film layer 20 off thefoam base 22) or in accordance with standardized test methods such asASTM D3330 or ASTM D903.

An active agent may be dispersed within the phase-separated polymer ofthe stem portion 12 and/or the head portion 18. Of course, the stemportion 12 and the head portion 18 may include different active agents.Further, if the stem portion 12 includes different sub portions, thesesub portions may include different active agents. In some examples, oneor more of the portions may be free of the active agent.

The various portions/films of the closure device 10 may each include theactive agent or drug, be substantially free of the drug, or free of thedrug. The term “substantially free” as used with reference to any of theactive agents or drugs described herein may be defined as less than 5,4, 3, 2, 1, 0.5, 0.1, 0.05, or 0.01 wt. %, based on a total weight of aparticular portion or on a total weight of the closure device 10. Thedisclosure that contemplates “substantially free of” also encompasses“free of”. As such, when the portions and/or closure device 10 aredescribed as “substantially free of” something, e.g. a drug, thisdescriptive language can be narrowed to “free of”.

The active agent may be located in the cell walls of the foamedphase-separated polymer. Alternatively, the active agent may be locatedwithin the voids of the foamed phase-separated polymer. When drugs arelocated within the cell walls of the pores, the porosity of theparticular drug containing foamed portion influences the release rate ofthe active agent. The higher the porosity, the higher the rate ofrelease and vice versa. Without wishing to be bound by theory, it isbelieved that an increased porosity results in an increased degradationrate of the phase-separated polymer and thereby an increased releaserate. In other words, the degradation of the phase-separated polymercontrols the release of the active agent.

The rate of release of the active agent from the phase-separated polymermay be expressed as the time required to release a certain amount ofdrug in a certain amount of time. Typically, 8 hours to 1.5 days arerequired to release 50% of the active agent from the foamed shellportion. In particular examples, it may be preferred that 50% of theactive agent is released in a longer time, e.g. in 1 to 5 days. Torelease about 100% (e.g. more than 95%) of the active agent, a time of 4to 14 days is generally preferred.

Typically, the active agent is a drug (i.e., any pharmaceutically activecompound), an antibiotics, an anti-inflammatory agent, a,corticosteroid, a hemostatic agent, an anti-allergen, ananti-cholinergic agent, an antihistamine, an anti-infective, ananti-platelet, an anti-coagulant, an anti-thrombic agent, ananti-scarring agent, an anti-proliferative agent, a chemotherapeuticagent, an anti-neoplastic agent, a pro-healing agent, decongestant, avitamin, a hyperosmolar agent, an immunomodulator, an immunosuppressiveagent, or combinations thereof.

In a preferred example, the active agent includes a molecule includingat least one hydrogen atom, which is bound to a nitrogen, oxygen, orfluorine atom. This structure facilitates hydrogen bonding between theactive agent and phase-separated polymer, e.g. the polyurethane foamcomprising the crystalline segments comprising the reaction product of1,4 butanediol and 1,4 diisocyanatobutane and the amorphous segmentscomprising poly(ethylene glycol). In other words, the active agent mayadvantageously include a polymer that includes hydrogen atoms that areavailable to form a hydrogen bond with the crystalline segments of thefirst and/or second polyurethane foam. Hydrogen bonding between theactive agent and the phase-separated polymer helps control and slow downthe release of the active agent.

In one example, the active agent is a steroidal anti-inflammatory agent.It has been found that the relatively slow release of the active agentfrom the phase-separated polymer is particularly suitable for steroidalanti-inflammatory agents, such as corticosteroids.

In another example, the active agent is a hemostatic agent. Of course,the closure device 10 may include both an anti-inflammatory agent, e.g.a steroid, and a hemostatic agent. In various examples, the hemostaticagent includes at least one hydrogen atom bonded to a nitrogen atom,and/or at least one hydrogen atom bonded to an oxygen atom, with thehydrogen atoms being available to form a hydrogen bond with thecrystalline segments of the first and/or second polyurethane foam. Insuch examples, molecules of the hemostatic agent and molecules of thephase-separated polymer are bonded to one another via hydrogen bondingand substantially free of covalent bonds therebetween.

In certain examples, the hemostatic agent is a chitosan hemostaticagent. The term “chitosan hemostatic agent” as used herein refers tochitosan or a salt or derivative thereof. Favorable results have beenobtained using chitosan or chitosan acetate.

Chitosan is a polysaccharide comprising D-glucosamine units(deacetylated units) and N-acetyl-D-glucosamine units (acetylatedunits). Chitosan may be prepared from chitin by deacetylating at leastpart of the N-acetyl-D-glucosamine in chitin(poly-N-acetyl-D-glucosamine) by hydrolysis. The ratio of D-glucosamineunits and N-acetyl-D-glucosamine units in chitosan is typicallyexpressed as the degree of deacetylation. The degree of deacetylation isdefined as the percentage of glucosamine units in chitosan that are notacetylated. This percentage thus corresponds to the molar percentage ofdeacetylated units present in chitosan.

Without being bound by theory, it is believed that a higher degree ofdeacetylation improves the hemostatic properties. The chitosan may havea degree of deacetylation of 1-100 mol %, 25-100 mol %, 50-100 mol %,75-100 mol %, 85-100 mol %, 90-100 mol %, 5-50 mol %, 10-35 mol %, or10-25 mol %. The above values also apply to chitosan present in chitosansalts, as well as to chitosan derivatives (which have acetylated anddeacetylated units just like chitosan itself). In additionalnon-limiting examples, all values and ranges of degree of deacetylationvalues within and including the aforementioned range endpoints arehereby expressly contemplated. Without being bound by theory, it isbelieved that a higher degree of deacetylation improves the hemostaticproperties of the chitosan.

Suitable chitosan salts are those with the chitosan ion having a netpositive charge. Accordingly, suitable chitosan salts may be saltsconsisting of a chitosan cation and a counter anion. For example, thechitosan hemostatic agent may be a salt of chitosan with an organicacid, in particular with a carboxylic acid such as succinic acid, lacticacid or glutamic acid. Chitosan salts may for example be selected fromthe group consisting of nitrate, phosphate, glutamate, lactate, citrate,acetate and hydrochloride salts of chitosan.

In general, a chitosan derivative is a chitosan molecule wherein one ormore of the hydroxyl groups and/or the amine group present in chitosanhas been substituted. For example, the one or more hydroxyl groups maybe substituted to obtain an ether or ester. The amine group may besubstituted to obtain an amino group, although this generally results ina decrease in hemostatic activity. Therefore, the amine groups ofchitosan are typically unsubstituted.

The chitosan hemostatic agent may include or be derived from chitosanoriginating from animals, plants or shellfish. These sources givesimilar good results with respect to the hemostatic effects describedabove. Furthermore, synthetic chitosan may also be used.

Further examples of suitable chitosan salts are chitosan esters ofglutamate, succinate, phthalate or lactate, chitosan derivativescomprising one or more carboxymethyl cellulose groups, carboxymethylchitosan. Other suitable examples of chitosan derivates are chitosanwith quaternary groups (like N-trimethylene chloride, N-trimethyleneammonium). In addition, bioactive excipients such as calcitonin or5-methylpyrrolidinone may be used.

The chitosan hemostatic agent may have a molecular weight in the rangeof about 1-1000 kDa, 1-500 kDa, 1-250 kDa, 1-100 kDa, 10-1000 kDa,10-500 kDa, 10-250 kDa, 10-100 kDa, 30-80 kDa, 50-1000 kDa, 50-500 kDa,50-350 kDa, 50-250 kDa, 100-1000 kDa, 100-750 kDa, 100-500 kDa, 100-250kDa, 150-500 Kda, 200-1000 kDa, 200-750 kDa, 200-500 kDa, 225-275 kDa,200-300 kDa, 210-390 kDa, 90-1000 kDa, 190-1000 kDa, 290-1000 kDa, or390-1000 kDa. In additional non-limiting examples, all values and rangesof molecular weight values within and including the aforementioned rangeendpoints are hereby expressly contemplated.

In certain examples, when the active agent is the hemostatic agent, thefoamed portion including the hemostatic agent (i.e., the foamed shellportion and/or the foamed core portion) has a porosity of 35-99%, or85-99% and a foam density of 0.03-1.1, or 0.03-0.07 g/cm³. Such valuesfor the porosity and density contribute to the enhanced hemostaticactivity and also provide the foam with good liquid (e.g. water orblood) absorbing properties. Alternatively, the foamed portion has aporosity of 92-98%, or 95-98% and a foam density of 0.03-0.07 g/cm³.

The amount of hemostatic agent may be at least 0.1 wt. %, preferably atleast 2 wt. %, more preferably at least 5. wt. % of the total weight ofthe foam portion comprising the hemostatic agent. Notably, even thisrelatively small amount of hemostatic agent is sufficient to provide thefoam nasal dressing with desirable hemostatic properties. Furthermore,the amount of hemostatic agent is generally less than 99 wt. %, lessthan 50 wt. %, or less than 35 wt. % of the total weight of the foamportion. Since the hemostatic activity of the foam nasal dressing isalmost independent on hemostatic agent, high concentrations aregenerally neither required nor preferred.

The hemostatic agent is preferably present in the foam in the form ofparticles, in particular polymeric particles. Examples of suitableparticles are amorphous, crystalline and gel-like particles. Thehemostatic agents may also be liquid, in particular when highly viscous.In case of hemostatic particles, the particles may have a size from1-1000 μm. Preferably, particles are smaller than 150 μm. In particulargood results have been obtained using particles of 5-90 μm. Smallparticles have a number of advantages. First, the structure of the foamis less influenced by the presence of small particles than largeparticles. Second, small hemostatic particles have a smaller tendency toaggregate than large particles. Furthermore, a good dispersion may beobtained using small particles. Lastly, small particles do not settledown when preparing the foam, such that a homogeneous distributionwithin the foam may be achieved if desirable.

The hemostatic particles may be any suitable shape, but are preferablyroughly spherical. The particles are preferably solid. Suitable solidparticles to be used are generally insoluble and hydrophilic.

The present disclosure also includes a method of making the closuredevice 10. In a typical example, the closure device 10 may be formed viaa phase separation method. That is, in some examples, phase separationof a polymer solution may be used to produce a polymer-rich domain and asolvent-rich domain, and this morphology may be fixed by quenching underlow temperature conditions. Removal of solvent through freeze-drying orextraction produces the phase-separated polymer. Phase separation may beinduced by changing the temperature or by adding non-solvent to thepolymer solution. In polyurethanes, hydrogen bonding between carbonyland N—H groups is one of the major driving forces for phase separation.

In one example, the method of forming the closure device 10 having thehead portion 18 and the stem portion 12 includes the step of providing amold defining a void space for forming the head and stem portions 12,18; placing a first liquid comprising a phase-separated polymer in themold; cooling the first liquid to freeze the first liquid; and dryingthe first liquid to form the closure device 10.

In another example, the method of forming the closure device 10 havingthe head portion 18 and the stem portion 12 includes the step ofproviding a mold defining a void space for forming the head and stemportions 12, 18; providing a spacer; placing the spacer at leastpartially into the mold; placing a first liquid comprising a firstphase-separated polymer in the mold; cooling the first liquid to freezethe first liquid; removing the spacer from the frozen first liquid toform a secondary void space; placing a second liquid in the secondaryvoid space; cooling the second liquid to freeze the second liquid; anddrying the first and second liquids to form the closure device 10.

The method may further include the step of placing the film layer 20over the first and or second liquids prior to the step(s) of freezing,after the step(s) freezing, or after the step(s) of drying.

The mold and/or the spacer may have a cavity of any suitable shapeand/or size. The mold and/or spacer may be formed from any suitablematerial. In examples where the closure device 10 includes one or morephase-separated polymers, the method may further include placing aspacer in the mold. Although the shape of the spacer is not particularlylimited, the shape should prevent the spacer from reaching the bottom ofthe cavity of the mold and should cooperate with the mold to besuspended in the void space as desired.

The method further includes placing a first and/or a second liquid inthe mold. The first liquid may include the first phase-separatedpolymer, a solvent, and optionally the active agent. The second liquidmay include the second phase-separated polymer (which may be the same asthe first phase-separated polymer), a solvent, and optionally the activeagent. When solvent is included, the first and/or second liquid suitablesolvents include polar solvents which have freezing points in the rangeof about 0-50° C. Such solvents may be removed by drying. Such suitablesolvents include organic solvents such as acetic acid, benzene,cyclohexane formic acid, nitrobenzene, phenol, 1,4-dioxane,1,2,4-trichlorobenzene, dimethylsulphoxide (DMSO) and combinationsthereof. In one example, the solvent used is 1,4-dioxane. When the firstand/or second liquid includes a solvent, the first liquid is typicallyformed by dissolving the first phase-separated polymer and the activeagent in the solvent. Of course, the spacer and the first liquid may beplaced in the mold in any order. When in the mold, the first liquid andthe spacer are in contact. In other words, the spacer displaces at leasta portion of the volume of the first liquid in the mold.

The method further includes cooling the first liquid to freeze the firstliquid. The cooling of the first liquid may be carried out at anysuitable temperature capable of freezing the first liquid. If the stepof freezing the second liquid is also included, the cooling of thesecond liquid may be carried out at any suitable temperature capable offreezing the second liquid.

The method further includes removing the spacer from the frozen firstliquid to expose a cavity in the frozen first liquid. To facilitateremoval of the spacer from the frozen first liquid, the spacer istypically formed of PTFE and generally cylindrically shaped. PTFE isadvantageous due to its inherent low frictional properties. In addition,using a generally cylindrically shaped spacer or spacer having anarcuate surface allows the spacer to be “spun” while being removed toloosen the spacer from the frozen first liquid without disrupting thephysical shape of the frozen first liquid.

In certain examples, drying is performed by lowering the pressure andincreasing the temperature such that any solvent present in first andsecond frozen liquids is sublimed from the phase-separated polymers. Insome examples, the temperature increase may be in part from the latentheat of sublimation of solvent molecules and may result in up to 90%,95%, or 100% of the solvent subliming. The entire freeze-drying processmay last from about 0.5 hour to 24 hours, or more.

In certain examples, when the active agent is not soluble in thephase-separated polymer or solvent, the method includes additional stepsto ensure a homogeneous incorporation of the active agent into theparticular foam portion. When the active agent is not soluble in thephase-separated polymer and/or solvent, the active agent is typically aparticle.

The present disclosure also includes a surgical tool 110 fortrans-nasally placing the closure device 10 in an opening 300 in theskull 302. Referring now to FIGS. 5 and 6, the surgical tool 110includes a body 112 defining an inner channel 114, the body 112 having ahandle 116, a dispensing tip 118, and a central section 120therebetween. The dispensing tip 118 has a tapered profile between afirst region 122 and a second region 124, the first region 122 having agreater diameter D₁₂₂ than the second region D₁₂₄. Alternatively, thedispensing tip 118 may be described as having a flared portion whichincludes the first region 122 and a second region 124. The flaredportion has an inner diameter, which increases along the longitudinalaxis A_(L) in a radial direction. A shaft 126 is moveably disposed inthe inner channel 114 of the body 112, the shaft 126 has a controlsurface 128 at a proximal region 130 and a deformable head 132 at adistal region 134, the shaft 126 and the deformable head 132 cooperateto define a lumen 136 to accommodate a portion of the closure device 10.

Referring now to FIGS. 7 and 8, upon actuation of the control surface128, the deformable head 132 moves between a first state in which thedeformable head 132 is outside of the second region 124 of thedispensing tip 118 and a second state where the deformable head 132 isat least partially within the second region 124 of the dispensing tip118, wherein a diameter of the deformable head 132 in the first state isgreater than a diameter of the deformable head 132 in the second state.

In a typical example, the deformable head 132 is conical when notdeformed. The deformable head 132 may have an inner surface with ahigher coefficient of friction which allows the head to grip onto theclosure device 10 during loading, and an outer surface with a lowercoefficient of friction so that the deformable head slides easily intothe lumen of the dispensing tip. The surface characteristics of theinner and outer surfaces of the deformable head 132 can be obtained byusing a multilayer head with different materials defining the inner andouter surfaces of the deformable head 132. Alternatively, various spraycoatings can be used to increase or decrease the lubricity or “grip”provided by the particular surface. In some examples, the inner surfaceof the deformable head 132 is patterned, e.g. with bumps or ridges, toimprove its grip on the closure device 10 during loading of the closuredevice 10 into the surgical tool 110.

Still referring to FIGS. 7 and 8, the dispensing tip 118 includes asidewall 138 that defines a void having a tapered profile, and wherein,upon actuation of the control surface 128, the shaft 126 is moveablewithin the inner channel 114 to move the deformable head 132 proximallysuch that the sidewall 138 of the dispensing tip 118 engages the stemportion 12 and deforms the head portion 18 to load the closure device 10into the surgical tool 110.

In FIG. 7B, the closure device 10 is in a free state FS and the headportion 18 has a diameter DF. In FIG. 8B, the closure device 10 is in adeformed state DS and the head portion 18 has a diameter DD that is lessthan the diameter DF. This allows for insertion of the closure deviceinto the opening 330 having a diameter which is smaller than thediameter DF of the head portion 18 in the free state FS.

Still referring to FIGS. 7 and 8, when the deformable head 132 is pulledproximally into the lumen 136 of the dispensing tip 118, the deformablehead 132 deforms. As such, the deformable head 132 typically comprises athermoplastic, a thermoplastic elastomer, or an elastomer. When thedeformable head 132 is pulled proximally into the lumen 136 of thedispensing tip 118, the closure device 10 likewise deforms. In a typicalexample, the stem portion 12 and the head portion 18 of the closuredevice 10 are compressed. Furthermore, the head portion 18 may bedeformed, collapsed, folded and/or compressed along the longitudinalaxis A_(L) in a distal direction. In other words, as the deformable head132 and the closure device 10 are pulled proximally into the lumen 136of the dispensing tip 118 along the longitudinal axis A_(L), the stemand head portions 12, 18 are being compressed and the head portion 18 isbeing collapsed distally along the longitudinal axis A_(L).

Still referring to FIGS. 7 and 8, the control surface 128 includes athumb stirrup 140 and a plurality of finger saddles 142. In thisexample, there are three finger saddles 142 a, 142 b, and 142 c. A usermay insert their thumb into the thumb stirrup 140 and loop their indexand middle fingers over the finger saddles 142 a, 142 b, and 142 c andactuate the surgical tool 110 with only one hand. Finger saddle 142 callows for single-handed actuation in a proximal direction to load theclosure device 10, while finger saddles 142 a, 142 b allow forsingle-handed actuation in a distal direction to release the closuredevice 10.

In a typical example, the dispensing tip 118 is formed separately fromthe central section 120 and is coupled thereto. In other examples, thedispensing tip 118 and the central section 120 are integral. Thedispensing tip 118 is typically conical. Further, the dispensing tip 118includes an alignment flange 144, wherein the alignment flange 144 isconfigured to rest on an outer surface 306 of the skull 302. That is,the alignment flange 144 rests on the outer surface 306 of the skull 302when the dispensing tip 118 is inserted into the opening 300 such thatthe closure device 10 is positioned in the opening 300 and does notpenetrate too far into a cranial cavity 310.

Referring now to FIG. 9, in some examples, the surgical tool 110includes the body 112 with the central section 120 comprising amalleable material, and the shaft 126 (not shown in FIG. 9) includes aflexible material such that a shape of the surgical tool 110 may bechanged to facilitate use of the surgical tool 110 in the nasal cavity298. In FIG. 9, the surgical tool 110 has a curved shape to facilitateits use in the nasal cavity 298.

Referring back to FIG. 6, the body 112 of the surgical tool 110 has aninner surface 146 which defines the inner channel 114 and also a stopsurface 148, wherein the shaft 126 includes a stop shelf 150 extendingradially therearound. The stop shelf 150 cooperates with the stopsurface 148 to stop movement of the shaft 126 along a longitudinal axisA_(L) in the distal direction.

The surgical tool 110 may, in many examples, be sterilized, e.g.autoclaved, and reused. That is, the materials used to form someexamples of the surgical tool 110 may withstand elevated temperature andhumidity. In other examples, the surgical tool 110 is disposable, andmay be discarded after use.

The present disclosure also includes a system for trans-nasally closingthe opening 300 in the base of the skull 302. The system includes theclosure device 10 for trans-nasally closing an opening 300 in a base ofthe skull 302 and the surgical tool 110 for trans-nasally placing theclosure device 10 in an opening 300 in the skull 302, both of which aredescribed in detail above. The system may be packaged and sold as a kit,with the kit including the surgical tool 110 and one or more of theclosure device 10. Of course, the one or more of the closure device 10can be packaged with, sub-packaged with, or packaged independently ofthe kit. The system may also include a supplemental kit which includesone or more of the closure device 10 since, in many examples, thesurgical tool 110 is designed to be sterilized, e.g. autoclaved, andreused.

The present disclosure also includes a method 500 of trans-nasallyclosing the opening 300 in the base of the skull/cranium 302 having theinner surface 304 defining the cranial cavity 310 with the closuredevice 10 (the closure device 10 is described in detail above). Themethod 500 of trans-nasally closing the opening 300 in the base of theskull/cranium 302 having the inner surface 304 defining the cranialcavity 310 with the closure device 10 in generally shown in FIG. 16. Themethod includes the step 502 of providing the closure device 10. Atleast the head portion 18 of the closure device 10 is deformed from afree shape to a deformed shape in step 504. Once deformed, in step 506the head portion 18 is inserted through a nasal cavity 298 and throughthe opening 300 such that the head portion 18 is in the cranial cavity310 and the stem portion 12 extends through the opening 300 and into thenasal cavity 298. Once released, in step 508 such that the closuredevice 10 at least partially reverts back to the free shape such thatthe stem portion 12 fills the opening 300 and the head portion 18 abutsthe inner surface 304 of the skull/cranium 302 as well as dura 308,thereby securing the closure device 10 in position and sealing theopening 300.

In addition to the step 502 of providing the closure device 10, themethod 500 may further include the step 510 of providing the surgicaltool 110 for closing the opening 300 in the skull/cranium 302 with theclosure device 10. The surgical tool 110 is just as previouslydescribed.

As set forth above, the method 500 includes the step 504 of deformingthe closure device 10 from a free shape to a deformed shape isillustrated in FIGS. 7A, 7B, 8A, and 8B. In FIGS. 7A and 7B, the closuredevice 10 is un-deformed in a free state. In FIGS. 8A and 8B, theclosure device 10 is deformed, for example, the head portion 18 of theclosure device 10 is folded along the longitudinal axis A_(L). It shouldbe appreciated, that the step 504 of deforming the head portion 18 ofthe closure device 10 from a free shape to a deformed shape may comprisefolding, as described above, or other means of deformation such ascompression. For example, the step 504 of deforming the closure device10 from a free shape to a deformed shape may comprise compressing thehead portion 18 and stem portion 12 of the closure device 10, which ispossible because the closure device 10 is foamed. As another example,the stem portion 12 and the head portion 18 can be compressed and thewith the head portion 18 of the closure device 10 can also be collapsedor folded along the longitudinal axis A_(L). Once compressed, theclosure device 10 may be inserted in position and released in step 508such that the closure device 10 at least partially reverts via expansionback to the free shape such that the stem portion 12 fills the opening300 and the head portion 18 abuts the inner surface 304 of theskull/cranium 302 as well as dura 308, thereby securing the closuredevice 10 in position and sealing the opening 300. In the examplesillustrated, the step 504 of deformation involves both folding andcompression of the closure device 10.

It is to be appreciated that deformation can involve collapsing,folding, and/or compressing the closure device 10. Although notillustrated, the stem portion 12 of the closure device 10 can becompressed up to 10, 20, 30, 40, 50, 60, or 70% by volume, e.g. in thedispending tip 118 of the surgical tool 110, during deformation. Assuch, the release of the closure device 10 can cause the stem portion 12substantially fill, or completely fill the opening 300. The head portion18 is often collapsed or folded along the longitudinal axis A_(L) andis, during the deformation process compressed too. In a typical example,the closure device 10 expands out into and fills the opening. Of course,the closure device 10 starts out in a first, undeformed state, and thenis compressed into a second, compressed state. On release, the closuredevice 10 at least partially reverts back to its uncompressed shape. Inmany examples, the closure device 10 does not totally revert back to itsoriginal uncompressed state due to the anatomical features of theparticular patient and other factors.

When the method 500 utilizes the surgical tool 110, the method 500 mayfurther include the step of loading the closure device 10 into thesurgical tool 110. The step of loading the closure device 10 in thesurgical tool 110 is illustrated in FIGS. 7A, 7B, 8A, and 8B. FIG. 7A isthe perspective view of the closure device 10 and the surgical tool 110prior to loading the closure device 10 in the surgical tool 110, andFIG. 7B is cross-sectional view of the closure device 10 and a distalend of the surgical tool 110 prior to loading. Whereas FIG. 8A is aperspective view of the closure device 10 loaded into a distal end ofthe surgical tool 110, and FIG. 8B is a cross-sectional view of theclosure device 10 loaded into the dispensing tip 118 of the surgicaltool 110. In such examples, the step 504 of deforming is further definedas moving the deformable head 132 proximally such that the dispensingtip 118 on the surgical tool 110 engages and deforms the stem portion 12and the head portion 18 to load the closure device 10 into the surgicaltool 110. Loading may be accomplished via a step of actuating a shaft onthe surgical tool 110 from a disengaged position (shown in FIGS. 7A and7B) to an engaged position (shown in FIGS. 8A and 8B) to deform theclosure device 10 from a free shape to a constricted shape and load theclosure device 10 within the dispensing tip 118. In some examples, theclosure device 10 is compressed during the step 504 of deformation (andthus expands during the step 508 of releasing).

Prior to or after loading, the method 500 may include the step ofbending the central section 120 of the surgical tool 110 to facilitateuse of the surgical tool 110 in the nasal cavity 298. In FIG. 9, thesurgical tool 110 has a curved shape to facilitate its use in the nasalcavity 298.

Referring now to FIGS. 10 and 11, when the method 500 utilizes thesurgical tool 110, the surgical tool 110 having the closure deviceloaded into the dispensing tip 118 is inserted into the nasal cavity 298and the deformed head portion 18 of the closure device 10 extendedthrough the nasal cavity 298 and into the opening 300 such that the headportion 18 of the closure device 10 is in the cranial cavity 310 and thestem portion 12 of the closure device 10 extends through the opening 300and into the nasal cavity 298. FIG. 10 is a perspective view of theclosure device 10 loaded into the surgical tool 110 as well as theopening 300 in a base of the skull 302, while FIG. 11 is across-sectional view of the deformed closure device 10 loaded into thesurgical tool 110, which is aligned in the opening 300 in the base ofthe skull 302.

Referring now to FIGS. 12-14, the shaft 126 may be actuated from anengaged position to a disengaged position to release the closure device10 in the opening 300. In FIG. 12, a cross-sectional view of thesurgical tool 110 and the closure device 10 deformed and partiallyreleased in the opening 300 in the base of the skull 302 is illustratedand in FIG. 13 a cross-sectional view of the surgical tool 110 and theclosure device 10 fully released in the opening 300 in the base of theskull 302 is illustrated. FIG. 14 is a cross-sectional view of theclosure device 10 released and at least partially reverted back to itsfree shape such that the stem portion 12 fills the opening 300 and thehead portion 18 abuts an inner surface 304 of the skull/cranium 302 aswell as dura 308, thereby securing the closure device 10 in position andsealing the opening 300.

Additional Formatted Disclosure: Surgical Tool

I. A surgical tool for trans-nasally placing a bioresorbable foamclosure device in an opening in a base of a skull, the closure devicehaving a stem portion and a head portion, the surgical tool comprising:

a body defining an inner channel, the body having a handle, a dispensingtip, and a central section therebetween, the dispensing tip having atapered profile between a first region and a second region, the firstregion having a greater diameter than the second region; and a shaftmoveably disposed in the inner channel of the body, the shaft having acontrol surface at a proximal region and a deformable head at a distalregion, the shaft and the deformable head cooperate to define a lumen toaccommodate a portion of the closure device;

wherein upon actuation of the control surface, the deformable head movesbetween a first state in which the deformable head is outside of thesecond region of the dispensing tip and a second state where thedeformable head is at least partially within the second region of thedispensing tip, wherein a diameter of the deformable head in the firststate is greater than a diameter of the deformable head in the secondstate.

II. The surgical tool as set forth in II. wherein the dispensing tipincludes sidewalls that define the tapered profile, and wherein uponactuation of the control surface the shaft moves proximally within theinner channel and the head moves proximally such that the sidewalls ofthe dispensing tip engage and deform the deformable head to load theclosure device into the surgical tool.

III. The surgical tool as set forth in claim I. or II. wherein thecontrol surface comprises a thumb stirrup.

IV. The surgical tool as set forth in claim III. wherein the controlsurface comprises a pair of finger saddles such that a user may inserttheir thumb into the thumb stirrup and loop their index and middlefingers over the finger saddles and actuate the surgical tool with onehand.

V. The surgical tool as set forth in any one of I. through IV. whereinthe dispensing tip is formed separately from the central section and iscoupled thereto.

VI. The surgical tool as set forth in any one of I. through V. whereinthe dispensing tip comprises an alignment flange, wherein the alignmentflange is configured to rest on an outer surface of the skull when thedeformable head is inserted into the opening such that the closuredevice is positioned in the opening and does not penetrate too far intoa cranial cavity.

VII. The surgical tool as set forth in any one of I. through VI. whereinthe central section of the body comprises a malleable material, and theshaft comprises a flexible material such that a shape of the surgicaltool may be changed to facilitate use of the surgical tool in a nasalcavity.

VIII. The surgical tool as set forth in any one of I. through VII.wherein the body has an inner surface which defines the inner channeland also a stop surface, wherein the shaft includes a stop shelfextending radially thereabout that cooperates with the stop surface tostop movement of the shaft along a longitudinal axis in the distaldirection.

IX. The surgical tool as set forth in any one of I. through IIX. whereinthe dispensing tip is conical.

X. The surgical tool as set forth in any one of I. through IX. whereinthe deformable head is conical when not deformed.

Additional Formatted Disclosure: Closure Device

I. A bioresorbable foam closure device for trans-nasally closing anopening in a base of a skull, the device comprising:

a stem portion having a proximal end and a distal end, the stem having afirst diameter; and

a head portion at the distal end having a second diameter being largerthan the first diameter;

wherein the head portion comprises a film layer and a foam layer,wherein a porosity of the film layer is greater than a porosity of thefoam layer;

wherein the film layer is disposed at a distal end of the closure deviceand the foam layer of the head is disposed between the film layer andthe stem portion;

wherein the head portion and the stem portion comprise a phase-separatedpolymer having a porosity of greater than 80%, the phase-separatedpolymer having the formula:

—[R-Q¹[—R′—Z¹—[R″—Z²—R′—Z³]_(p)—R″—Z⁴]_(q)—R′-Q²]_(n)-  (I)

wherein R is selected from one or more aliphatic polyesters,polyetheresters, polyethers, polyanhydrides and/or polycarbonates, andoptionally at least one R comprises a hydrophilic segment, R′ and R″ areindependently C₂-C₈ alkylene, optionally substituted with C₁-C₁₀ alkylor C₁-C₁₀ alkyl groups substituted with halides or protected S, N, P orO moieties and/or comprising S, N, P or O in the alkylene chain, Z¹—Z⁴are independently amide, urea or urethane, Q¹ and Q² are independentlyurea, urethane, amide, carbonate, ester or anhydride, n is an integerfrom 5-500, p and q are independent 0 or 1, provided that when q is 0, Ris at least one amorphous aliphatic polyester, polyether, polyanhydrideand/or polycarbonate segment with optionally at least one crystallinepolyether, polyester, polyetherester or polyanhydride segment;

wherein the closure device is deformed from a free shape to aconstricted shape, inserted through a nasal cavity and into the opening,and released to at least partially revert back to the free shape suchthat the stem portion fills the opening and the head portion abuts aninner surface of the skull as well as dura, thereby securing the closuredevice in position and sealing the opening.

II. The bioresorbable closure device as set forth I. wherein the headportion is foldable along a longitudinal axis in a distal direction.

III. The closure device as set forth in any one of claims I. or II.further comprising at least one active agent.

IV. The closure device as set forth in any one of I. through III.wherein the stem portion and or the head portion has a cylindricalshape.

V. The closure device as set forth in any one of I. through IV. whereinthe stem portion is cylindrical and the head portion is concentricallydisposed on the distal end of the stem portion and disc shaped.

VI. The closure device as set forth in any one of I. through V. whereinthe stem portion and/or the head portion has a rectangularcross-sectional profile.

VII. The closure device as set forth in any one of I. through VI.wherein the film layer comprises polysiloxane.

VIII. The closure device as set forth in any one of I. through VII.wherein the film layer comprises polyurethane.

IX. The closure device as set forth in VII. wherein the film layer andthe foam base are bonded to one another via hydrogen bonding andsubstantially free of covalent bonds therebetween.

X. The closure device as set forth in any one of I. through IX. whereinremoval of the film layer from the foam base results in cohesive failureof the foam base at a bond interface therebetween.

XI. The closure device as set forth in any one of I. through X. whereina bond interface between the film layer and the foam base is free ofadhesive.

XII. The closure device as set forth in any one of I. through IX.wherein the phase-separated polymer is independently selected from thegroup consisting of polyesters, polyethers, polyhydroxyacids,polylactones, polyetheresters, polycarbonates, polydioxanes,polyanhydrides, polyurethanes, polyester(ether)urethanes, polyurethaneurea, polyamides, polyesteramides, poly-orthoesters, polyaminoacids,polyphosphonates, polyphosphazenes, and combinations thereof.

XIII. The closure device as set forth in any one of I. through XII.wherein the phase-separated polymer is a polyurethane foam includingamorphous segments and crystalline segments, the crystalline segmentsformed via hydrogen bonding.

XIV. The closure device as set forth in XIII wherein the crystallinesegments in the polyurethane foam comprise a reaction product of 1,4butanediol and 1,4 diisocyanatobutane.

XV. The closure device as set forth in XIII or XIV. wherein theamorphous segments in the polyurethane foam comprise a polyalkyleneglycol.

XVI. The closure device as set forth in XV. wherein molecules within thepolyurethane foam are arranged so that that the crystalline segments andthe amorphous segments stack in an alternating configuration to providea 3-dimentional porous structure which is strengthened via hydrogenbonding between the stacked crystalline segments.

One or more of the values described above may vary by ±5%, ±10%, ±15%,±20%, ±25%, etc., so long as the variance remains within the scope ofthe disclosure. Each member may be relied upon individually and or incombination and provides adequate support for specific examples withinthe scope of the appended claims. The subject matter of all combinationsof independent and dependent claims, both singly and multiply dependent,is herein expressly contemplated. The disclosure is illustrative,including words of description rather than of limitation. Manymodifications and variations of the present disclosure are possible inlight of the above teachings, and the disclosure may be practicedotherwise than as specifically described herein.

All combinations of the aforementioned examples throughout the entiredisclosure are hereby expressly contemplated in one or more non-limitingexamples even if such a disclosure is not described verbatim in a singleparagraph or section above. In other words, an expressly contemplatedexample may include any one or more elements described above selectedand combined from any portion of the disclosure.

It is also to be understood that any ranges and subranges relied upon indescribing various examples of the present disclosure independently andcollectively fall within the scope of the appended claims, and areunderstood to describe and contemplate all ranges including whole and/orfractional values therein, even if such values are not expressly writtenherein. One of skill in the art readily recognizes that the enumeratedranges and subranges sufficiently describe and enable various examplesof the present disclosure, and such ranges and subranges may be furtherdelineated into relevant halves, thirds, quarters, fifths, and so on. Asjust one example, a range “of from 0.1 to 0.9” may be further delineatedinto a lower third, i.e. from 0.1 to 0.3, a middle third, i.e. from 0.4to 0.6, and an upper third, i.e. from 0.7 to 0.9, which individually andcollectively are within the scope of the appended claims, and may berelied upon individually and/or collectively and provide adequatesupport for specific examples within the scope of the appended claims.In addition, with respect to the language which defines or modifies arange, such as “at least,” “greater than,” “less than,” “no more than,”and the like, it is to be understood that such language includessubranges and/or an upper or lower limit. As another example, a range of“at least 10” inherently includes a subrange of from at least 10 to 35,a subrange of from at least 10 to 25, a subrange of from 25 to 35, andso on, and each subrange may be relied upon individually and/orcollectively and provides adequate support for specific examples withinthe scope of the appended claims. Finally, an individual number within adisclosed range may be relied upon and provides adequate support forspecific examples within the scope of the appended claims. For example,a range “of from 1 to 9” includes various individual integers, such as3, as well as individual numbers including a decimal point (orfraction), such as 4.1, which may be relied upon and provide adequatesupport for specific examples within the scope of the appended claims.

Several examples have been discussed in the foregoing description.However, the examples discussed herein are not intended to be exhaustiveor limit the invention to any particular form. The terminology which hasbeen used is intended to be in the nature of words of description ratherthan of limitation. Many modifications and variations are possible inlight of the above teachings and the invention may be practicedotherwise than as specifically described.

1. A system for trans-nasally closing an opening in a base of a skull,the system including: a bioresorbable foam closure device fortrans-nasally closing an opening in a base of a skull, the devicecomprising a stem portion having a proximal end and a distal end, and ahead portion at the distal end having at least one dimension beinglarger than the stem portion, the stem portion comprising a firstphase-separated polymer having amorphous segments and crystallinesegments, and the head portion comprising a second phase-separatedpolymer having amorphous segments and crystalline segments, the firstphase-separated polymer and the second phase-separated polymer being thesame or different, wherein the stem portion is formed from aphase-separated polymer and has a porosity of greater than 80%; and asurgical tool comprising: a body defining an inner channel, the bodyhaving a handle, a dispensing tip, and a central section therebetween,the dispensing tip having a tapered profile between a first region and asecond region, the first region having a greater diameter than thesecond region; and a shaft moveably disposed in the inner channel of thebody, the shaft having a control surface at a proximal region and adeformable head at a distal region, the shaft and the deformable headcooperate to define a lumen to accommodate a portion of the closuredevice.
 2. The system as set forth in claim 1, wherein the head portionis collapsible along a longitudinal axis in a distal direction.
 3. Thesystem as set forth in claim 1, wherein the first and/or secondphase-separated polymer is a polyurethane foam including the amorphoussegments and the crystalline segments, wherein the crystalline segmentsare formed via hydrogen bonding.
 4. The system as set forth in claim 1,wherein the bioresorbable foam closure device further comprises at leastone active agent.
 5. The system as set forth in claim 1, wherein thehead and the stem portions share a longitudinal axis and a radius of thehead portion relative to the longitudinal axis is greater than a radiusof the stem portion relative to the longitudinal axis.
 6. The system asset forth in claim 1, wherein the head portion comprises a film layerand a foam base.
 7. The system as set forth in claim 6, wherein: aporosity of the film layer is less than a porosity of the foam base;and/or the film layer is disposed at the distal end of the closuredevice and the foam base of the head is disposed between the film layerand the stem portion.
 8. (canceled)
 9. The system as set forth in claim1, wherein: the stem portion and/or the head portion has a cylindricalshape; and/or the head portion has a greater perimeter and/or diameterthan the stem portion.
 10. (canceled)
 11. The system as set forth inclaim 1, wherein the dispensing tip includes sidewalls that define thetapered profile, and wherein upon actuation of the control surface, theshaft is moveable within the inner channel to move the deformable headproximally such that the sidewalls of the dispensing tip engage anddeform the deformable head to load the closure device into the surgicaltool.
 12. The system as set forth in claim 1, wherein the controlsurface comprises: a thumb stirrup; and/or a pair of finger saddles,such that a user may insert their thumb into the thumb stirrup and looptheir index and middle fingers over the finger saddles and actuate thesurgical tool with one hand.
 13. (canceled)
 14. The system as set forthin claim 1, wherein the distal end of the body includes a flared portionhaving a diameter, which increases along a longitudinal axis in a radialdirection.
 15. The system as set forth in claim 1, wherein the distalend of the body includes an alignment flange, wherein the alignmentflange rests on an outer surface of the skull when the dispensing tip isinserted into the opening such that the closure device is positioned inthe opening and does not penetrate too far into a cranial cavity. 16.The system as set forth in claim 1, wherein the central section of thebody comprises a malleable material and the shaft comprises a flexiblematerial such that a shape of the surgical tool may be changed tofacilitate use of the surgical tool in a nasal cavity.
 17. The system asset forth in claim 1, wherein the body has an inner surface whichdefines the inner channel and also a stop surface, wherein a stop shelfextends radially around the shaft and cooperates with the stop surfaceto stop movement of the shaft along a longitudinal axis in a distaldirection.
 18. A method of trans-nasally closing an opening in a base ofa cranium having an inner surface and defining a cranial cavity with asurgical tool and a bioresorbable foam closure device, said methodcomprising the steps of: providing the closure device having a stemportion having a proximal end and a distal end, and a head portion atthe distal end having at least one dimension being larger than the stemportion, the stem portion comprising a first phase-separated polymerhaving amorphous segments and crystalline segments, and the head portioncomprising a second phase-separated polymer having amorphous segmentsand crystalline segments, the first phase-separated polymer and thesecond phase-separated polymer being the same or different, wherein thestem portion is formed from a phase-separated polymer and has a porosityof greater than 80%; deforming at least the head portion of the closuredevice from a free shape to a deformed shape; inserting the deformedhead portion of the closure device through a nasal cavity and throughthe opening such that the head portion is in the cranial cavity and thestem portion extends through the opening and into the nasal cavity; andreleasing the closure device such that the closure device at leastpartially reverts to the free shape such that the stem portion fills theopening and the head portion abuts an inner surface of the cranium aswell as dura, thereby securing the closure device in position andsealing the opening.
 19. The method as set forth in claim 18, furthercomprising the step of providing a surgical tool for closing the openingin a skull with the closure device.
 20. The method as set forth in claim19, further comprising the step of loading the closure device into thesurgical tool, and wherein the step of deforming is further defined asmoving the deformable head proximally such that a dispensing tip on thesurgical tool engages the stem portion of the closure device and deformsthe deformable head to load the closure device into the surgical tool.21. The method as set forth in claim 20, further comprising the step ofactuating a shaft on the surgical tool from a disengaged position to anengaged position to deform the closure device from a free shape to aconstricted shape and load the closure device within a dispensing tip.22. The method as set forth in claim 21, further comprising the step ofactuating the shaft from an engaged position to a disengaged position torelease the closure device in the opening.
 23. The method as set forthin claim 20, wherein the closure device is compressed during the step ofdeformation and expands during the step of release.